Disease relevance of phosphocitrate

• Phosphocitrate, which is a poor chelator of Ca2+, did not reduce the hypercalcemia induced by either agent [1].
• The present study was undertaken to examine the role of calcification in OA disease progression and to evaluate a formulation of phosphocitrate (PC) as a potential therapeutic agent [2].
• Phosphocitrate, a phosphorylated polycarboxylic acid ameliorates two early events in atherogenesis [3].
• These results give further clues as to how PC inhibits the progression of ankylosis in MPA [4].
• The recently described phosphocitrate in a mixed calcium and sodium salt, yet to be tested in a guinea pig osteoarthritis model, appears to be an even more powerful inhibitor [5].

High impact information on phosphocitrate

• Administration of phosphocitrate greatly reduced the net uptake of Ca2+ by the kidneys and prevented the appearance of apatite-like crystalline structures within the mitochondrial matrix and cytosol of renal tubule cells [1].
• The induction of both COX-2 and IL-1beta by BCP crystals was attenuated when the cells were treated with phosphocitrate [6].
• Phosphocitrate (PC) can specifically block mitogenesis and proto-oncogene expression induced by either BCP or CPPD crystals in 3T3 cells and human fibroblasts, suggesting that PC may be an effective therapy for calcium deposition diseases [7].
• Inhibition of calcium pyrophosphate dihydrate crystal formation in articular cartilage vesicles and cartilage by phosphocitrate [8].
• Phosphocitrate prevents disease progression in murine progressive ankylosis [9].

Biological context of phosphocitrate

• This paper reports the synthesis of phosphocitric acid via the phosphorylation of triethyl citrate with o-phenylene phosphochloridate, hydrogenolysis of the product to yield triethyl phosphocitrate, hydrolytic removal of the blocking ethyl groups and also chromatographic purification [10].
• We found that basic calcium phosphate (BCP) crystals greatly stimulated the endocytotic activity of cells by rendering the cells more permeable and that the anti-calcification agent phosphocitrate and several others inhibited the crystals-mediated endocytosis [11].
• The adsorption of citrate and phosphocitrate ions by hydroxyapatite (HAP) surfaces and their influence on the constant composition growth kinetics of HAP have been investigated [12].

Anatomical context of phosphocitrate

• These crystals are mitogenic and induce protooncogene expression and matrix metalloproteinase (MMP) synthesis and secretion in human fibroblasts, effects that are specifically blocked by phosphocitrate (PC) [13].
• Exposure of cultured cells to crystals induces expression of cellular proto-oncogenes such as c-fos, c-myc and c-jun, by a calcium-dependent mechanism, and this response can be blocked by a potential therapeutic compound, phosphocitrate [14].
• The present study reports the influence of a phosphorylated polycarboxylic acid, phosphocitrate, on low density lipoprotein (LDL) metabolism in cultured rabbit aortic smooth muscle cells [15].
• Atherogenesis. Mitigation of monocyte adhesion to arterial endothelium in hyperlipidemic rats by phosphocitrate, a phosphorylated polycarboxylic acid [3].
• Recognition of the existence of a biologically synthetic pathway adds credence to the known presence of phosphocitrate in mitochondria and a postulated role to control calcium phosphate deposition in that organelle [16].

Associations of phosphocitrate with other chemical compounds

• Decreasing the pH from 7.4 to 7.2 produced similar solubility changes as did the addition of citrate at 0.3 mM, phosphocitrate at 0.3 mM, ATP at 0.1 mM, and the bisphosphonate, HEBP, at 0.1 mM [17].
• This inhibition was specific for crystal-induced mitogenesis, since similar concentrations of phosphocitrate had no effects on either PDGF or 10% calf serum-induced thymidine incorporation and c-fos transcription [18].
• Calcium oxalate (CaOx) crystallization in the presence of phosphocitrate (PC) was studied by both in vitro and in vivo techniques [19].

Gene context of phosphocitrate

• METHOD: Using a semi-quantitative reverse transcription-polymerase chain reaction method and phosphocitrate (PC), a specific inhibitor of the biological effects of BCP crystals, we examined the effects of BCP on the steady state transcript levels of metalloproteinase (MMP)-1, -3, -9 and -13 and TIMP-1 and -2 in human fibroblasts [20].
• PC, at 10(-3) mol/L, inhibited the TGF-beta 1-induced proliferation of MPA and 3T3 cells, but had no effect on normal fibroblasts [4].

Analytical, diagnostic and therapeutic context of phosphocitrate

• These in vivo observations therefore indicate that phosphocitrate acts primarily at the cellular level to prevent the extensive accumulation of calcium phosphate in kidney cells by inhibiting the mitochondrial accumulation or crystallization of calcium phosphate [1].
• Transmission electron microscopy of aortic sections showed no evidence of subendothelial lipid accumulation in phosphocitrate-treated rats despite the high circulating plasma lipid levels [3].
• Scanning electron microscopy and molecular modeling of inhibition of calcium oxalate monohydrate crystal growth by citrate and phosphocitrate [21].
• The current formulations demonstrate that the therapeutic efficacy of phosphocitrate can be markedly improved through an appropriately designed drug delivery system, signalling a new approach for the future therapeutic application of this compound [22].

References